The present invention is in the field of medicine, particularly in the treatment of Type II diabetes and obesity. More specifically, the present invention relates to xcex23 adrenergic receptor agonists useful in the treatment of Type II diabetes and obesity.
The current preferred treatment for Type II, non-insulin dependent diabetes as well as obesity is diet and exercise, with a view toward weight reduction and improved insulin sensitivity. Patient compliance, however, is usually poor. The problem is compounded by the fact that there are currently no approved medications that adequately treat either Type II diabetes or obesity.
One therapeutic opportunity that has recently been recognized involves the relationship between adrenergic receptor stimulation and anti-hyperglycemic effects. Compounds that act as xcex23 receptor agonists have been shown to exhibit a marked effect on lipolysis, thermogenesis and serum glucose levels in animal models of Type II (non-insulin dependent) diabetes.
The xcex23 receptor, which is found in several types of human tissue including human fat tissue, has roughly 50% homology to the xcex21 and xcex22 receptor subtypes yet is considerably less abundant. Stimulation of the xcex21 and xcex22 receptors can cause adverse effects such as tachycardia, arrhythmia, or tremors. An agonist that is selective for the xcex23 receptor over the xcex21 and xcex22 receptors is, therefore, more desirable for treating Type II diabetes or obesity relative to a non-selective agonist.
However, recent studies have suggested the presence of an atypical beta receptor associated with atrial tachycardia in rats (Br. J. of Pharmacol., 118:2085-2098, 1996). In other words, compounds that are not agonists of the xcex21 and xcex22 receptors can still modulate tachycardia through activation of a yet to be discovered xcex24 or through some other unknown pathway.
A large number of publications have appeared in recent years reporting success in discovery of agents that stimulate the xcex23 receptor. For example, U.S. Pat. No. 5,786,356 discloses xcex23 agonists of the formula: 
wherein:
R1 can be, among other things, a moiety of the formula: 
A1 and A2 can be, among other things, NH, CH2, NCH3, or NCH2CH3; and
R4 can be, among other things, a moiety of the formula: 
Despite these recent developments, there remains a need to develop a selective xcex23 receptor agonist which has minimal agonist activity against the xcex21 and xcex22 receptors and which displays a minimal propensity to cause atrial tachycardia.
The present invention relates to a compound of formula I: 
wherein:
R1 is H, CN, halo, C1-C6 alkyl, C1-C4 haloalkyl, CO2R8, CONHR8, NHCOR8, NHR8, OR8, SR8, SOR8, SO2R8 or SO2NHR8;
R1a is H, halo or C1-C6 alkyl;
R2 is H, C1-C6 alkyl or benzyl;
R3 is C1-C6 alkyl or benzyl;
or R2 and R3 combine with the carbon to which each are attached to form a C3-C7 carbocyclic ring; provided that if R3 is C2-C6 alkyl or benzyl, then R2 must be hydrogen;
R4 is H or C1-C6 alkyl;
R5 and R6 are independently H or C1-C6 alkyl; or
R5 and R6 combine with the carbon to which each are attached to form a C3-C6 carbocyclic ring;
or R6 combines with X1, the carbon to which both are attached, and the phenyl group to which X1 is attached to form a moiety selected from the group consisting of: 
wherein:
m and n are independently 0, 1, 2, or 3 provided that the sum of n+q is xe2x89xa65 and that R5 is H;
R7 is hydrogen, optionally substituted phenyl or optionally substituted heterocycle;
R8 is H or C1-C6 alkyl;
X is OCH2, SCH2 or a bond; and
X1 is a bond or a C1-C5 divalent hydrocarbon moiety; and
X2 is O, S, NH, NHSO2, SO2NH, CH2 or a bond; or a pharmaceutical salt thereof.
The present invention also relates to processes for preparing, as well as novel pharmaceutical formulations containing, a compound of formula I. In another embodiment, the pharmaceutical formulations of the present invention may be adapted for use in treating Type II diabetes and obesity and for agonizing the xcex23 receptor.
The present invention also relates to methods for treating Type II diabetes and obesity, as well as a method for agonizing the xcex23 receptor employing a compound of formula I.
In addition, the present invention relates to a compound of formula I for use in treating Type II diabetes and obesity as well as a compound of formula I for use in agonizing the xcex23 receptor. The present invention is further related to the use of a compound of formula I for the manufacture of a medicament for treating Type II diabetes and obesity as a well as for agonizing the xcex23 receptor.
The present invention is also related to a compound of formula II: 
which is useful as an intermediate to prepare a compound of formula I.